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Identification of long non-coding RNAs in neuronal development and intellectual disability

Eva D'haene (UGent) , Eva Jacobs (UGent) , Pieter-Jan Volders (UGent) , Björn Menten (UGent) and Sarah Vergult (UGent)
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Abstract
Recent studies have assigned important functions to lncRNAs in gene regulation and protein interactions. Since many of these lncRNAs emerged recently during vertebrate and primate evolution, a crucial role in the human brain is anticipated. Here, we aimed at identifying candidate lncRNAs associated with neuronal development and intellectual disability (ID). To do this, we combined the latest genomic annotations of lncRNAs (i.e. LNCipedia database) with functional data (neuron-specific H3K4 trimethylation, REST binding & DNaseI hypersensitivity). These three datasets were applied as filters, both to RefSeq protein-coding genes and LNCipedia lncRNA transcripts. To assess the specificity of these potential filters, we performed an enrichment analysis of ID genes and genome wide association study (GWAS) hits for central nervous system (CNS) disorders, on the resulting sets of protein-coding genes (ID genes & GWAS hits) and lncRNA transcripts (GWAS hits only). We found the neuron-specific H3K4me3 mark to confer the highest specificity for genes involved in ID and neurodevelopment. Applying this mark as a filter for all LNCipedia transcripts resulted in a set of 4188 lncRNAs, of which 53 harbour a GWAS hit for CNS disorders. As the presence of such a SNP directly implicates these lncRNA loci in neuropathogenesis, we focused during subsequent analyses on this set of 53 lncRNAs. This approach was complemented by extensive expression profiling of all protein-coding genes and ca. 23,000 lncRNA transcripts in 15 human tissues, among which 8 different brain samples. This allowed us to construct coexpression profiles for 30 of the lncRNAs that were identified by our filtering strategy (no unique probes could be designed for the other 23 transcripts). Using Gene Set Enrichment Analysis (GSEA) we evaluated the involvement of the selected lncRNAs in neuronal processes. For 19 out of the 30 selected lncRNAs, gene sets linked to synaptic transmission, nervous system development or neurogenesis were highly enriched among the top positively correlated genes. Five lncRNAs were negatively correlated to genes involved in these neuronal processes, suggesting that these lncRNAs may be involved in suppressive regulation. In conclusion, we set up a strategy to identify lncRNAs involved in neuronal development and 30 interesting lncRNA transcripts remained. The relevance of our strategy was underscored by the fact that at least 24 of these lncRNAs are implicated in neuronal processes through correlated expression profiles. In our further research we will validate these top candidates by targeted functional analysis.

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Chicago
D’haene, Eva, Eva Jacobs, Pieter-Jan Volders, Björn Menten, and Sarah Vergult. 2016. “Identification of Long Non-coding RNAs in Neuronal Development and Intellectual Disability.” In Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging Voor Humane Genetica (NVHG), 1st Joint Meeting, Abstract Book.
APA
D’haene, E., Jacobs, E., Volders, P.-J., Menten, B., & Vergult, S. (2016). Identification of long non-coding RNAs in neuronal development and intellectual disability. Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging voor Humane Genetica (NVHG), 1st Joint meeting, Abstract book. Presented at the 1st Joint meeting of the Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging voor Humane Genetica (NVHG): Genetics and society.
Vancouver
1.
D’haene E, Jacobs E, Volders P-J, Menten B, Vergult S. Identification of long non-coding RNAs in neuronal development and intellectual disability. Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging voor Humane Genetica (NVHG), 1st Joint meeting, Abstract book. 2016.
MLA
D’haene, Eva, Eva Jacobs, Pieter-Jan Volders, et al. “Identification of Long Non-coding RNAs in Neuronal Development and Intellectual Disability.” Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging Voor Humane Genetica (NVHG), 1st Joint Meeting, Abstract Book. 2016. Print.
@inproceedings{7173342,
  abstract     = {Recent studies have assigned important functions to lncRNAs in gene regulation and protein interactions. Since many of these lncRNAs emerged recently during vertebrate and primate evolution, a crucial role in the human brain is anticipated. Here, we aimed at identifying candidate lncRNAs associated with neuronal development and intellectual disability (ID). 
To do this, we combined the latest genomic annotations of lncRNAs (i.e. LNCipedia database) with functional data (neuron-specific H3K4 trimethylation, REST binding & DNaseI hypersensitivity). These three datasets were applied as filters, both to RefSeq protein-coding genes and LNCipedia lncRNA transcripts. To assess the specificity of these potential filters, we performed an enrichment analysis of ID genes and genome wide association study (GWAS) hits for central nervous system (CNS) disorders, on the resulting sets of protein-coding genes (ID genes & GWAS hits) and lncRNA transcripts (GWAS hits only). We found the neuron-specific H3K4me3 mark to confer the highest specificity for genes involved in ID and neurodevelopment. Applying this mark as a filter for all LNCipedia transcripts resulted in a set of 4188 lncRNAs, of which 53 harbour a GWAS hit for CNS disorders. As the presence of such a SNP directly implicates these lncRNA loci in neuropathogenesis, we focused during subsequent analyses on this set of 53 lncRNAs.
This approach was complemented by extensive expression profiling of all protein-coding genes and ca. 23,000 lncRNA transcripts in 15 human tissues, among which 8 different brain samples. This allowed us to construct coexpression profiles for 30 of the lncRNAs that were identified by our filtering strategy (no unique probes could be designed for the other 23 transcripts). Using Gene Set Enrichment Analysis (GSEA) we evaluated the involvement of the selected lncRNAs in neuronal processes. For 19 out of the 30 selected lncRNAs, gene sets linked to synaptic transmission, nervous system development or neurogenesis were highly enriched among the top positively correlated genes. Five lncRNAs were negatively correlated to genes involved in these neuronal processes, suggesting that these lncRNAs may be involved in suppressive regulation.
In conclusion, we set up a strategy to identify lncRNAs involved in neuronal development and 30 interesting lncRNA transcripts remained. The relevance of our strategy was underscored by the fact that at least 24 of these lncRNAs are implicated in neuronal processes through correlated expression profiles. In our further research we will validate these top candidates by targeted functional analysis.},
  author       = {D'haene, Eva and Jacobs, Eva and Volders, Pieter-Jan and Menten, Björn and Vergult, Sarah},
  booktitle    = {Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging voor Humane Genetica (NVHG), 1st Joint meeting, Abstract book},
  language     = {eng},
  location     = {Leuven, Belgium},
  title        = {Identification of long non-coding RNAs in neuronal development and intellectual disability},
  year         = {2016},
}